The Role of YAP and TAZ in Angiogenesis and Vascular Mimicry

Abstract

Angiogenesis, the formation of new blood vessels from pre-existing vasculature, is a physiological process that begins in utero and continues throughout life in both good health and disease. Understanding the underlying mechanism in angiogenesis could uncover a new therapeutic approach in pathological angiogenesis. Since its discovery, the Hippo signaling pathway has emerged as a key player in controlling organ size and tissue homeostasis. Recently, new studies have discovered that Hippo and two of its main effectors, Yes-associated protein (YAP) and its paralog transcription activator with PDZ binding motif (TAZ), play critical roles during angiogenesis. In this review, we summarize the mechanisms by which YAP/TAZ regulate endothelial cell shape, behavior, and function in angiogenesis. We further discuss how YAP/TAZ function as part of developmental and pathological angiogenesis. Finally, we review the role of YAP/TAZ in tumor vascular mimicry and propose directions for future work.

Keywords: Hippo pathway; LATS1/2; MST1/2; TAZ; YAP; angiogenesis; cancer; vascular mimicry.

Figure 1

Tumor angiogenesis. In tumor cells, several signaling pathways such as phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) can phosphorylate eIF4E1 to increase the HIF-1α translational level. Also, direct phosphorylation and hydroxylation are two important post-translational modifications that cause HIF-1 dimerization and promote its degradation, respectively. Activated HIF-1 then functions as a master switch to induce the expression of several growth factors such as VEGF, PDGF, and Ang2, as well as extracellular matrix proteases such as matrix metalloproteinase (MMP). MMPs allow the endothelial cells to escape into the interstitial matrix during sprouting angiogenesis. Also, secreted growth factors induce survival, proliferation, migration, and vascular permeability in endothelial cells. Abbreviations—PHD: prolyl hydroxylase domain protein; ATM: ataxia telangiectasia mutated; HRE: HIF-1 response elements; HIF-1: hypoxia-inducible factor 1; MMP: matrix metalloproteinase; VEGF: vascular endothelial growth-factor; VEGFR: VEGF receptor; PDGF: platelet-derived growth factor.

Figure 2

An overview of the regulation of YAP and TAZ transcriptional co-activators. YAP and TAZ are downstream mediators of numerous signaling pathways such as G-protein couple receptors (GPCRs) and epidermal growth factor (EGFR). YAP and TAZ localization is mainly regulated through phosphorylation by large tumor suppressor (LATS). The 14-3-3 phosphobinding protein interacts with and sequesters phosphorylated YAP and TAZ. YAP and TAZ localization is also regulated through physical interaction, for example with SMAD, β-catenin, and junction proteins. YAP: Yes-associated protein (YAP); TAZ: transcription activator with PDZ binding motif.

Figure 3

An overview of the regulation of YAP and TAZ transcriptional co-activators in angiogenesis. Several receptors regulate YAP and TAZ activity directly via LATS or other unknown pathways, which can affect angiogenesis. VEGFR regulates YAP and TAZ through three main pathways including the Rho GTPase, MAPK, and PI3K pathway. The TGF-β, Wnt, and CD44 pathways regulate YAP and TAZ as well as LATS activity through several not well-known mechanisms. Abbreviations—TF: transcription factor; ECM: extracellular matrix; Fz: frizzled receptor.